Not Applicable
This invention relates generally to a method of treating hyperproliferative diseases, and in particular, to the use of active forms of hypocalcemic vitamin D to inhibit the hyperproliferative cellular activity of these diseases and to promote differentiation of the cells.
Extensive research during the past two decades has established important biologic roles for vitamin D apart from its classic role in bone and mineral metabolism. Specific nuclear receptors for 1xcex1,25-dihydroxyvitamin D3, the hormonally active form of vitamin D, are present in cells from diverse organs not involved in calcium homeostasis. For example, specific, biologically active vitamin D receptors have been demonstrated in the human prostatic carcinoma cell line, LNCaP, (Miller et al., 52 Cancer Res. (1992) 515-520); Vitamin D receptors have also been described for many other neoplastic cells, e.g., carcinomas of the breast and the colon.
It has been reported that certain vitamin D compounds and analogues are potent inhibitors of malignant cell proliferation and are inducers/stimulators of cell differentiation. For example, U.S. Pat. No. 4,391,802 issued to Suda et al. discloses that 1xcex1-hydroxyvitamin D compounds, specifically 1xcex1,25-dihydroxyvitamin D3 and 1xcex1-hydroxyvitamin D3, possess potent antileukemic activity by virtue of inducing the differentiation of malignant cells (specifically leukemia cells) to nonmalignant macrophages (monocytes), and are useful in the treatment of leukemia. Antiproliferative and differentiating actions of 1xcex1,25-dihydroxyvitamin D3 and other vitamin D3 analogues have been reported with respect to cancer cell lines. More recently, an association between vitamin D receptor gene polymorphism and cancer risk has been reported, suggesting that vitamin D receptors may have a role in the development, and possible treatment, of cancer.
These previous studies have focused exclusively on vitamin D3 compounds. Even though these compounds may indeed be highly effective in promoting differentiation in malignant cells in culture, their practical use in differentiation therapy as anticancer agents is severely limited because of their equally high potency as agents affecting calcium metabolism. At the levels required in vivo for effective use as, for example, antileukemic agents, these same compounds can induce markedly elevated and potentially dangerous blood calcium levels by virtue of their inherent calcemic activity. That is, the clinical use of 1xcex1,25-dihydroxyvitamin D3 and other vitamin D3 analogues as anticancer agents is precluded, or severely limited, by the risk of hypercalcemia. This indicates a need for compounds with greater specific activity and selectivity of action, i.e., vitamin D compounds with antiproliferative and differentiating effects but which have less calcemic activity.
The present invention provides a method of treating hyperproliferative disease conditions such as those characterized by hyperproliferative cell growth and/or abnormal cell differentiation. The method includes use of active vitamin D compounds to inhibit abnormal cell growth and promote cell differentiation.
The foregoing, and other advantages of the present invention, are realized in one aspect thereof in a method of inhibiting the hyperproliferative activity of neoplastic or hyperplastic cells, comprising treating the cells with an effective amount of a hypocalcemic vitamin D compound. The treating step includes inhibiting proliferation of, and inducing and enhancing differentiation in such cells.
The hypocalcemic vitamin D compounds of the present invention include vitamin D compounds having a hydrocarbon moiety substituted at the C-24 position on the sidechain of the molecule and a hydroxy group substituted in at least one of the C1, C24 or C25 positions.
The vitamin D compound of the present invention is an active vitamin D and is suitably represented by the formula (I) described hereafter. The compounds of formula (I) suitably include 1xcex1,24-dihydroxyvitamin D2, 1xcex1,24-dihydroxyvitamin D4, 1xcex1,25-dihydroxyvitamin D4, 1xcex1,25-dihydroxyvitamin D2, 1xcex1-hydroxyvitamin D2 and 1xcex1-hydroxyvitamin D4.
Hypocalcemic vitamin D compounds are valuable for the treatment of breast and colon cancer, as well as other neoplasms such as pancreatic cancer, endometrial cancer, small cell and non-small cell cancer of the lung (including squamous, adneocarcinoma and large cell types), squamous cell cancer of the head and neck, bladder, ovarian and cervical cancers, myeloid and lymphocyltic leukemia, lymphoma, hepatic tumors, medullary thyroid carcinoma, multiple myeloma, melanoma, retinoblastoma, and sarcomas of the soft tissue and bone.
In accordance with the present invention, when effective amounts of hypocalcemic vitamin D compounds are administered to patients with cancer or neoplasms, the proliferative activity of the abnormal neoplastic cells is inhibited, reduced, or stabilized, and cell differentiation is induced, promoted or enhanced, with significantly less hypercalcemia and hypercalciuria than is observed after the same amount of an activated vitamin D3 (e.g., 1xcex1-OH D3, 1xcex1,25-(OH)2 D3) is administered in previously known formulations. Thus, the compound in accordance with the present invention has an improved therapeutic index relative to active forms of vitamin D3 analogues.
Accordingly, another aspect of the invention is a method of treating human cancer comprising administering to a subject who has cancer an effective amount of hypocalcemic vitamin D compound which has or attains through metabolism in vivo, a vitamin D receptor (VDR) binding affinity substantially equivalent to the binding affinity of 1xcex1,25-dihydroxyvitamin D3 and a hypercalcemia risk substantially lower that that of 1xcex1,25-dihydroxyvitamin D3, to inhibit, decrease or stabilize the cellular abnormal proliferative activity of the cancer.
For treatment for malignant conditions in accordance with the present invention, the hypocalcemic vitamin D compounds can be suitably administered alone as an active ingredient, as an antiproliferative agent in a pharmaceutical composition, or co-administered with an anticancer agent.
Further, included within the scope of the present invention is the co-administration of the vitamin D of formula (I) with a cytotoxic or anticancer agent. Such agents suitably include antimetabolites (e.g., 5-fluoro-uracil, methotrexate, fludarabine), antimicrotubule agents (e.g., vincristine, vinblastine, taxanes such as paclitaxel, docetaxel), an alkylating agent (e.g., cyclophasphamide, melphalan, biochoroethylnitrosurea, hydroxyurea), platinum agents (e.g. cisplatin, carboplatin, oxaliplatin, JM-216, CI-973), anthracyclines (e.g., doxrubicin, daunorubicin), antibiolitics (e.g., mitomycin, idarubicin, adriamycin, daunomycin), topoisomerase inhibitiors (e.g., etoposide, camptothecins) or any other antineoplastic agents. (estramustine phosphate, prednimustine).
It is anticipated that the hypocalcemic vitamin D compounds used in combination with various anticancer drugs can give rise to a significantly enhanced cytotoxic effect on cancerous cells, thus providing an increased therapeutic effect. Specifically, as a significantly increased growth-inhibitory effect is obtained with the above disclosed combinations utilizing lower concentrations of the anticancer drugs compared to the treatment regimes in which the drugs are used alone, there is the potential to provide therapy wherein adverse side effects associated with the anticancer drugs are considerably reduced than normally observed with the anticancer drugs used alone in larger doses. Possible dose ranges of these co-administered anticancer agents are about 0.1 to 20 mg/kg/day.
Also included within the scope of the present invention is the co-administration of effective dosages of the analogue of formula (I) in conjunction with administration of hormones or other agents, e.g., estrogens, which are known to ameliorate bone diseases or disorders. For example, prostate cancer often metastasizes to bone, causing bone loss and associated pain. Such bone agents may include conjugated estrogens or their equivalents, calcitonin, bisphosphonates, calcium supplements, cobalamin, pertussis toxin and boron.
In another aspect, the invention is a pharmaceutical composition which includes an anticancer agent which is an active vitamin D compound; an agent selected from the group consisting of (i) an anticancer agent, (ii) a bone agent, and combinations thereof; and a physiologically acceptable carrier.
Other advantages and a fuller appreciation of specific adaptations, compositional variations, and physical attributes will be gained upon an examination of the following detailed description of preferred embodiments, taken in conjunction with the appended claims.
Not Applicable
The present invention provides an effective method for the treatment of neoplasms and hyperproliferative diseases. Particularly, the present invention relates to therapeutic methods for inhibiting, reducing or stabilizing the hyperproliferative cellular activity of diseased cells, and inducing, enhancing or promoting cell differentiation in the diseased cells. The present invention provides a novel treatment of a patient suffering from a hyperproliferative disease such as prostatic cancer or prostatic hyperplasia with a hypocalcemic hydroxyvitamin D analogue. The vitamin D analogue is suitably a 1xcex1-hydroxyvitamin D or a 24-hydroxyvitamin D compound. The hypocalcemic hydroxyvitamin D analogue represented by formula (I) as described hereinbelow is provided to the patient without causing dose-limiting hypercalcemia and hypercalciuria, i.e., unphysiologically high and deleterious blood calcium levels and urine calcium levels, respectively. These attributes are achieved through specific chemical properties of the hypocalcemic vitamin D compounds as described.
In accordance with the present invention, when effective amounts of the hypocalcemic vitamin D compounds are administered to patients with cancer or hyperplasia, the proliferative activity of the abnormal cells is inhibited, maintained, or alleviated, and cell differentiation is induced, promoted or enhanced, with significantly less hypercalcemia and hypercalciuria than is observed after the same amount of activated vitamin D3 is administered in previously known formulations. Thus, the hypocalcemic vitamin D compounds of the present invention have an improved therapeutic index relative to active forms of vitamin D3 analogues.
It is known that vitamin D3 must be hydroxylated in the C-1 and C-25 positions before it is activated, i.e., before it will produce a biological response. A similar metabolism appears to be required to activate other forms of vitamin D, e.g., vitamin D2 and vitamin D4. Therefore, as used herein, the term xe2x80x9cactivated vitamin Dxe2x80x9d or xe2x80x9cactive vitamin Dxe2x80x9d is intended to refer to a vitamin D compound or analogue that has been hydroxylated in at least the C-1, C-24 or C-25 position of the molecule and either the compound itself or its metabolites in the case of a prodrug, such as 1xcex1-hydroxyvitamin D2, binds the vitamin D receptor (VDR). For example, vitamin D xe2x80x9cprodrugsxe2x80x9d include compounds which are hydroxylated in the C-1 position. Such compounds undergo further hydroxylation in vivo and their metabolites bind the VDR.
The term xe2x80x9chypocalcemic vitamin D compoundxe2x80x9d is in reference to active vitamin D analogs which demonstrate reduced calcemic activity relative to the calcemic activity of 1xcex1,25-dihydroxyvitamin D3. Such compounds include 24-hydroxyvitamin D compounds, 25-hydroxyvitamin D compounds and 1xcex1-hydroxyvitamin D compounds. The calcemic activity of these compounds ranges from 0.001 to 0.5 that of 1xcex1,25-dihydroxyvitamin D3.
Also, as used herein, the term xe2x80x9clowerxe2x80x9d as a modifier for alkyl, alkenyl acyl, or cycloalkyl is meant to refer to a straight or branched, saturated or unsaturated hydrocarbon radical having 1 to 4 carbon atoms. Specific examples of such hydrocarbon radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, propenyl, butenyl, isobutenyl, isopropenyl, formyl, acetyl, propionyl, butyryl or cyclopropyl. The term xe2x80x9caromatic acylxe2x80x9d is meant to refer to a unsubstituted or substituted benzoyl group.
As used herein, the term xe2x80x9chydrocarbon moietyxe2x80x9d refers to a lower alkyl, a lower alkenyl, a lower acyl group or a lower cycloalkyl, i.e., a straight or branched, saturated or unsaturated C1-C4 hydrocarbon radial.
The compound in accordance with the present invention is an active hypocalcemic vitamin D compound. Further, the active vitamin D in accordance with the present invention may have an unsaturated sidechain, e.g., there is suitably a double bond between C-22 and C-23, between C-25 and C-26 or between C-26 and C-27.
A hypocalcemic hydroxyvitamin D of the present invention has the general formula described in formula (I): 
wherein A1 and A2 each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23; R1 and R2 are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that both R1 and R2 cannot both be an alkenyl, or taken together with the carbon to which they are bonded, form a C3-C8 cyclocarbon ring; R3 is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl; X1 is hydrogen or hydroxyl, X2 is hydrogen or hydroxyl, or, may be taken with R1 or R2, to constitute a double bond, X3 is hydrogen or hydroxyl provided that at least one of X1, X2 and X3 is hydroxyl; and Y is a methylene group if the bond to Y is a double bond or is a methyl group or hydrogen if the bond to Y is a single bond.
A 1xcex1-hydroxyvitamin D compound of formula (I) is characterized by the general formula (II): 
wherein A1 and A2 each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23; R1 and R2 are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that both R1 and R2 cannot both be an alkenyl, or taken together with the carbon to which they are bonded, form a C3-C8 cyclocarbon ring; R3 is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl; X1 is hydrogen or hydroxyl, X2 is hydrogen or hydroxyl, or, may be taken with R1 or R2, to constitute a double bond, and Y is a methylene group if the bond to Y is a double bond or is a methyl group or hydrogen if the bond to Y is a single bond.
Specific 1xcex1-hydroxyvitamin D compounds in accordance with the present invention are characterized by the general formula (III): 
wherein A1 and A2 each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23; R1 and R2 are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that both R1 and R2 cannot both be an alkenyl, or taken together with the carbon to which they are bonded, form a C3-C8 cyclocarbon ring; R3 is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl; X1 is hydrogen or hydroxyl, and X2 is hydrogen or hydroxyl, or, may be taken with R1 or R2, to constitute a double bond.
The hypocalcemic vitamin D compounds of the present invention are those that have effective antiproliferative and cell differentiation activity (i.e., reversal of malignant transformation), but have a lower tendency or inability to cause the undesired side effects of hypercalcemia and/or hypercalciuria. In other words, the compounds of the present invention can be administered at dosages that allow them to act as antiproliferative agents and cell differentiation agents when exposed to malignant or other hyperproliferative cells without significantly altering calcium metabolism. This selectivity and specificity of action makes the hypocalcemic vitamin D compounds useful and preferred agents for safely inhibiting hyperproliferation and promoting malignant or hyperplastic cell differentiation. The compounds of the present invention, thus, overcome the shortcomings of the known active vitamin D3 compounds described above, and can be considered preferred agents for the control and treatment of malignant diseases such breast, prostate, testicular and colon cancer, as well as other neoplasms such as pancreatic cancer, endometrial cancer, small cell and non-small cell cancer of the lung (including squamous, adneocarcinoma and large cell types), squamous cell of the head and neck, bladder, ovarian and cervical cancers, myeloid and lymphocyltic leukemia, lymphoma, hepatic tumors, medullary thyroid carcinoma, multiple myeloma, melanoma, retinoblastoma, and sarcomas of the soft tissue and bone, i.e. neoplasms that express a vitamin D receptor.
Thus, the present invention provides a method of treating malignant cells as well as other hyperproliferative cells, (i.e., inhibiting their hyperproliferative activity and/or inducing and enhancing their differentiation) with an effective amount of a hypocalcemic vitamin D compound. The effective dosage amount on a daily basis per kilogram of body weight of the patient ranges from about 0.01 xcexcg/kg/day to about 2.0 xcexcg/kg/day. The compounds in accordance with the present invention can be given in daily dose or episodic dose, e.g., once every 2-6 days or once a week, the dose in each day can be a single dose or divided into 2-4 subdoses which can be given, e.g., an hour apart until the total dose is given. The compounds in accordance with the present invention are administered in an amount that raises a serum vitamin D level to a supraphysiological level for a sufficient period of time to induce differentiation or regression of a tumor or neoplasm with causing hypercalcemia. The hypocalcemic properties of the compound permit such supraphysiologic levels.
The compounds of formula (I) are valuable for the treatment of cancer and neoplasms in a patient suffering therefrom. In particular, the invention is a method for treating a patient suffering from the hyperproliferative cellular effects of cancer and other neoplasms by administering to the patient a therapeutically effective amount of a compound of formula (I), which is suitably 1xcex1,24-dihydroxyvitamin D2, 1xcex1,24-dihydroxyvitamin D4, 1xcex1,25-dihydroxyvitamin D2, 1xcex1,25-dihydroxyvitamin D4, 1xcex1-hydroxyvitamin D2, and 1xcex1-hydroxyvitamin D4. Among those compounds of formula (I) that have a chiral center in the sidechain, such as at C-24, it is understood that both epimers (e.g., R and S) and the racemic mixture are within the scope of the present invention.
The compounds of formula (I) can be prepared as described, e.g., in U.S. Pat. No. 5,488,120 issued to Knutson et al., U.S. Pat. Nos. 4,554,106, 4,670,190 and 5,486,636 issued to DeLuca et al., and Strugnell et al., 310 Biochem. J. (1995) pp.233-241, all of which are incorporated herein by reference.
The biopotencies of the compounds of formula (I) have been studied and compared to that of 1xcex1,25-dihydroxyvitamin D3, the active hormonal form of vitamin D and the standard against which all vitamin D compounds and analogues are measured. For example, it has been found that the vitamin D receptor (VDR) binding affinities of the compounds of formula (I), or their active metabolites, are substantially equivalent to (i.e., equal to or up to 3 times weaker than) the affinity of 1xcex1,25-dihydroxyvitamin D3. Such receptor binding affinities are indicative of potent biological activity.
At the same time, it has been found that compounds of formula (I) are significantly less toxic than their corresponding vitamin D3 analogues. For example, in parent co-pending application, Ser. No. 08/265,438, the disclosure of which is incorporated herein by reference, the LD50 for 1xcex1-hydroxyvitamin D4 was found to be 1.0 mg/kg in males and 3.0 mg/kg in females, i.e., substantially less toxic than 1xcex1-hydroxyvitamin D3 (LD50xcx9c0.2 mg/kg). Further, in the parent U.S. Pat. No. 5,403,831, and its grandparent U.S. Pat. No. 5,104,864, both of which are incorporated herein by reference, it has been shown that 1xcex1-hydroxyvitamin D2 has the same biopotency as 1xcex1-hydroxyvitamin D3 and 1xcex1,25-dihydroxyvitamin D3 but is much less toxic. Even dosages up to 10 xcexcg/day of 1xcex1-hydroxyvitamin D2 in women with postmenopausal osteoporosis elicited only mild hypercalciuria (U.Ca greater than 300 mg/24 hrs), and no marked hypercalcemia (S. Ca greater than 11.0 mg/dL) solely due to 1xcex1-hydroxyvitamin D2 was evident. Additionally, the compound did not adversely affect kidney function, as determined by creatinine clearance and BUN; nor did it increase urinary excretion of hydroxyproline, indicating the absence of any stimulatory effect on bone resorption. Administration of 1xcex1-hydroxyvitamin D2 to healthy adult males in dosages up to 8 xcexcg/day showed no clinically significant hypercalcemia or other adverse effects.
The compounds of formula (I) are useful as active ingredients in pharmaceutical compositions having reduced side effects and low toxicity as compared with the known analogues of active forms of vitamin D3.
The pharmacologically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, e.g., mammals including humans. For example, the hypercalcemic vitamin D compounds of the present invention can be employed in admixtures with conventional excipients, e.g., pharmaceutically acceptable carrier substances suitable for enteral (e.g., oral), parenteral or topical application which do not deleteriously react with the active compounds.
Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils (e.g., almond oil, corn oil, cottonseed oil, peanut oil, olive oil, coconut oil), mineral oil, fish liver oils, oily esters such as Polysorbate 80, polyethylene glycols, gelatine, carbohydrates (e.g., lactose, amylose or starch), magnesium stearate, talc, silicic acid, viscous paraffin, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc.
The pharmaceutical preparations can be sterilized and, if desired, be mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or one or more other active compounds, for example, vitamin D3 and its 1xcex1-hydroxylated metabolites, conjugated estrogens or their equivalents, anti-estrogens, calcitonin, biphosphonates, calcium supplements, cobalamin, pertussis toxin and boron.
For parenteral application, particularly suitable are injectable, sterile solutions, preferably oily or aqueous solution, as well as suspensions, emulsions, or implants, including suppositories. Parenteral administration suitably includes subcutaneous, intramuscular, or intravenous injection, nasopharyngeal or mucosal absorption, or transdermal absorption. Where indicated, the compounds of formula (I) may be given by direct injection into the tumor, e.g., parathyroid adenoma, or by regional delivery, e.g., by intraarterial delivery or delivery via the portal vein. Regional delivery is especially suitable for treatment of hepatic cancers. Ampoules are convenient unit dosages.
For enteral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, lozenges, powders, or capsules. A syrup, elixir, or the like can be used if a sweetened vehicle is desired.
For topical application, suitable nonsprayable viscous, semi-solid or solid forms can be employed which include a carrier compatible with topical application and having a dynamic viscosity preferably greater than water, for example, mineral oil, almond oil, self-emulsifying beeswax, vegetable oil, white soft paraffin, and propylene glycol. Suitable formulations include, but are not limited to, creams, ointments, lotions, solutions, suspensions, emulsions, powders, liniments, salves, aerosols, transdermal patches, etc., which are, if desired, sterilized or mixed with auxiliary agents, e.g., preservatives, stabilizers, demulsifiers, wetting agents, etc. A cream preparation in accordance with the present invention suitably includes, for example, mixture of water, almond oil, mineral oil and self-emulsifying beeswax; an ointment preparation suitably includes, for example, almond oil and white soft paraffin; and a lotion preparation suitably includes, for example, dry propylene glycol.
Topical preparations of the compound in accordance with the present invention useful for the treatment of skin disorders may also include epithelialization-inducing agents such as retinoids (e.g., vitamin A), chromanols such as vitamin E, xcex2-agonists such as isoproterenol or cyclic adenosine monophosphate (cAMP), anti-inflammatory agents such as corticosteroids (e.g., hydrocortisone or its acetate, or dexamethasone) and keratoplastic agents such as coal tar or anthralin. Effective amounts of such agents are, for example, vitamin A about 0.003 to about 0.3% by weight of the composition; vitamin E about 0.1 to about 10%; isoproterenol about 0.1 to about 2%; cAMP about 0.1 to about 1%; hydrocortisone about 0.25 to about 5%; coal tar about 0.1 to about 20%; and anthralin about 0.05 to about 2%.
For rectal administration, the compound is formed into a pharmaceutical composition containing a suppository base such as cacao oil or other triglycerides. To prolong storage life, the composition advantageously includes an antioxidant such as ascorbic acid, butylated hydroxyanisole or hydroquinone.
For treatment of calcium metabolic disorders, oral administration of the pharmaceutical compositions of the present invention is preferred. Generally, the compound of this invention is dispensed by unit dosage form comprising about 0.5 xcexcg to about 25 xcexcg in a pharmaceutically acceptable carrier per unit dosage. The dosage of the compound according to this invention generally is about 0.01 to about 1.0 xcexcg/kg/day, preferably about 0.04 to about 0.3 xcexcg/kg/day. Oral dosing for the treatment of cancers and neoplasms and other hyperproliferative diseases generally is about 10 xcexcg to 200 xcexcg/day.
For topical treatment of skin disorders, the dosage of the compound of the present invention in a topical composition generally is about 0.01 xcexcg to about 50 xcexcg per gram of composition. For treatment of cancers, the dosage of the hypocalcemic vitamin D compound in a locally applied composition generally is about 0.01 xcexcg to 100 xcexcg per gram composition.
Oral administration of the pharmaceutical compositions of the present invention is preferred. The dosage of the compounds for the treatment of cancer or neoplasms according to this invention generally is about 0.01 to about 2.0 xcexcg/kg/day, preferably about 0.01 to about 1.0 xcexcg/kg/day. As noted above, dosing of the hypocalcemic vitamin D compounds in accordance with the present invention can be done on an episodic basis, in which higher does can be used, generally about 20 xcexcg to about 200 xcexcg given once every 2-7 days. Generally, the compounds of this invention are dispensed by unit dosage form in a pharmaceutically acceptable carrier.
Those of ordinary skill in the art will readily optimize effective doses and coadministration regimens as determined by good medical practice and the clinical condition of the individual patient. Regardless of the manner of administration, it will be appreciated that the actual preferred amounts of active compound in a specific case will vary according to the efficacy of the specific compound employed, the particular compositions formulated, the mode of application, and the particular situs and organism being treated. For example, the specific dose for a particular patient depends on age, body weight, general state of health, on diet, on the timing and mode of administration, on the rate of excretion, and on medicaments used in combination and the severity of the particular disorder to which the therapy is applied. Dosages for a given host can be determined using conventional considerations, e.g., by customary comparison of the differential activities of the subject compounds and of a known agent, such as by means of an appropriate conventional pharmacological protocol.
Further, included within the scope of the present invention is a method of co-administration of hypercalemic vitamin D compounds with an anticancer or antineoplastic agent. Such agents may suitably include antimetabolites (e.g., 5-fluoro-uracil, methotrexate, fludarabine), antimicrotubule agents (e.g., vincristine, vinblastine, taxanes such as paclitaxel, docetaxel), an alkylating agent (e.g., cyclophasphamide, melphalan, biochoroethylnitrosurea, hydroxyurea), platinum agents (e.g. cisplatin, carboplatin, oxaliplatin, JM-216, CI-973), anthracyclines (e.g., doxrubicin, daunorubicin), antibiolitics (e.g., mitomycin, idarubicin, adriamycin, daunomycin), topoisomerase inhibitiors (e.g., etoposide, camptothecins) or any other antineoplastic agents. (estramustine phosphate, prednimustine). It is anticipated that hypercalcemic vitamin D compounds used in combination with various anticancer drugs can give rise to a significantly enhanced cytotoxic effect on cancerous cells, thus providing an increased therapeutic effect. Specifically, as a significantly increased growth-inhibitory effect is obtained with the above disclosed combinations utilizing lower concentrations of the anticancer drugs compared to the treatment regimes in which the drugs are used alone, there is the potential to provide therapy wherein adverse side effects associated with the anticancer drugs are considerably reduced than normally observed with the anticancer drugs used alone in larger doses. Possible dose ranges of these co-administered anticancer agents are about 0.1 to 20 mg/kg/day.
The term xe2x80x9cco-administrationxe2x80x9d is meant to refer to any administration route in which two or more agents are administered to a patient or subject. For example, the agents may be administered together, or before or after each other. The agents may be administered by different routes, e.g., one agent may be administered intravenously while the second agent is administered intramuscularly, intravenously or orally. The agents may be administered simultaneously or sequentially, as long as they are given in a manner sufficient to allow both agents to achieve effective concentrations in the body. The agents also may be in an admixture, as, for example, in a single tablet. In sequential administration, one agent may directly follow administration of the other or the agents may be give episodically, i.e., one can be given at one time followed by the other at a later time, typically within a week. An example of a suitable co-administration regimen is where a hypocalcemic vitamin D compound is administered from 0.5 to 7 days prior to administration of a cytotoxic agent.
Also included within the scope of the present invention is the co-administration of effective dosages of hypercalcemic vitamin D compounds in conjunction with administration of hormones or other agents, e.g., estrogens, which are known to ameliorate bone diseases or disorders. For example, prostate cancer often metastasizes to bone, causing bone loss and associated pain. Such bone agents may include conjugated estrogens or their equivalents, calcitonin, bisphosphonates, calcium supplements, cobalamin, pertussis toxin and boron. Possible dose ranges for these co-administered bone agents are provided in Table 1.
The present invention is further explained by the following examples which should not be construed by way of limiting the scope of the present invention.